PROJECT SUMMARY Building on our track record in genomic research, clinical trials, and genomic medicine in diverse, underserved patients from NYC, we propose to develop new frameworks to bring genomic risk into clinical care to promote health equity. Polygenic risk scores (PRS) are entering an exciting phase where they are poised to improve health outcomes for myriad complex diseases through enhanced risk stratification and clinical decision making. However, major challenges exist for clinical PRS implementation today. The vast majority of PRS have far greater predictive value in individuals of European ancestry than other ancestries, and issues of access to leading-edge genomic technology, research, and testing disproportionately impact underserved populations. To address this, Mount Sinai experts in statistical genetics and population genetics, with decade-long experience in building methods tailored to diverse and admixed populations, will work together to rigorously develop multi-ethnic PRS. We will integrate multi-ethnic PRS with standard clinical risk and family history information to generate genomic risk assessments for 15 common diseases. Drawing on Mount Sinai's century of experience serving one of the most diverse patient populations in the world, we will recruit 2,500 adult and pediatric patients from diverse and underserved populations into a clinical trial. We will estimate participants' individualized risk for each condition, and investigate the impact of genomic risk communication to patients and their physicians, including patient understanding and uptake of recommended risk-reducing interventions. We will explore attitudes, barriers, and communication preferences related to genomic risk assessment in diverse populations. Knowledge gained will be used to guide the development of a new multilingual patient-facing digital platform supporting patient education and communication of genomic risk. We will track patient engagement with their results through the platform, and assess the impact of individualized genomic risk assessments on patient-reported psychosocial outcomes and experiences. As of today, the path to effectively integrate genomic risk into clinical care in busy health systems, particularly for diverse patients, is unclear. Hence, we are partnering with clinicians, scientists, industry experts, and community stakeholders to explore a range of strategies to assess, communicate, and reduce disease risk, in order to maximize the efficiency of genomic medicine delivery, and promote health equity.